Method for the peeparation of



Patented Sept. 15, 1953 METHOD FOR THE PREPARATION OF LACTONES 4 Laurent Lucien Crabalon a, Grasse, France, as-

signor to Societe Anonyme des Etablissements Roure-Bertrand Fils & Justin Dupont, Paris, France, a corporation of the French Republic No Drawing. Application August 13, 1948, Serial No. 44,227. In France September 20, 1947 3 Claims.

Monocyclic lactones having more than 12 chain members in the lactone ring were studied at length by Kerschbaum (German Patent No. 449,217 of the 6th of March 1926 and Ber. Deutsch. Chem. Ges. 1927, vol. 60, pp. 902 ff.) who showed that they could not be obtained by the ordinary methods of esterification because such methods gave rise to polymers without interest.

The special procedure described by Kerschbaum consists in heating under particular conditions the silver salts of halogenated fatty acids in which the halogen atom is in at least the 12th position in relation to the carboxyl group. In this way three lactones having an odor of musk were prepared, the 1,15-pentadecanolide, the 1,16-hexadecanolide and the 1,16 hexadecene- 7-o1ide (ambrottolide), but the yields obtained were not reported.

Since that time other methods have been worked out for the preparation of these lactones, particularly the following:

a. The oxidation of cyclic ketones (Ruzicka and Stoll Helv. Chim. Acta 1928, 11, 1159; cf. also French Patent No. 657,971 of the 23rd of July 1928).

b.The internal ring-closure of oxyacids in a highly diluted medium (French Patent No. 773,651 of the 3rd of September 1934 and Certificate of Addition No, 46,623 of the 19th of May 1934).

c. The depolymerization of the corresponding polyesters (French Patents No. 768,807 of the 28th of May 1934 and No. 796,410 of the 22nd of January 1936) d. The treatment of certain halogenated fatty acids in an alkaline medium and in the presence of certain low boiling point solvents (French Patent No. 839,188 of the 11th of June 1933 of Hunsdiacher, Erlbach and Vogt).

e. The heating of an ester of an oxyacid in the presence of a catalyst of the exchange of functional groups (French Patent No. 830,689 of the 13th of December 1937 and Certificate of Addition No. 49,302 of the th of March 1938) etc.

The practical operation of these methods presents various inconveniences such as extreme dilution, the use of high vacua, the need for using special apparatus, the use of uncommon reagents, extreme slowness of the reactions, decomposition of the products, etc. It should be added that the yields also are not always satisfactory and that the quality of the lactones obtained leaves something to be desired, which is a particularly serious shortcoming in products intended for perfumery,

The process of the present invention is a process for the preparation of these lactones which is simple and rapid in operation; which uses standard apparatus and common reagents; and finally which gives these lactones with very great purity and a high yield.

This process is based on a reaction of internal double decomposition of certain esters in the presence of catalysts favoring the exchange of functional groups. A double decomposition reaction of this kind for the preparation of oranic esters was proposed in United States of America Patent No. 1,860,092 of the 31st of October 1929 George Graves assignor to E. I. du Pont de Nemours and Co.

In this patent it is stated that an ester of composition R OOO-R can be prepared by the interaction of two esters R. COOR, and R COO--R in the presence of a catalyst of the exchange of radicals; R -COO and Rfi-COO being the anions of carboxylic acids; R and R being alkyl radicals; the equilibrium equation is the following in which R is a chain containing at least 11 carbon atoms. This radical R can be split into two parts R or R each representing an open chain containing at least 5 carbon atoms; the above ester can then be formulated as In this form it presents a striking analogy with an equimolecular mixture of the esters Experience has shown that in certain conditions which will be specified later, this body (i. e. the diester) behaves exactly like such a mixture in forming the lactone V The present invention, the

which, replacing once more R for Rfi-I-Rfi, can be "If R and R are radicals containing few carbon atoms, the ester R -COO-R is very volatile, it escapes from the reaction zone, the equilibriurn is disturbed and the Reaction II proceeds from left to right yielding the desired lactone.

Experience has also shown that the Reaction II can proceed in the same way if the carboxylic anion R -COO-' is replaced by a mineral anion AQ- able to form a very volatile ester with the alcohol R. Ol-I; in that case the equation becomes 7 or, what comes to the same thing mechanism of which has just been explained, is thus essentially characterised by the decomposition, which can be regarded as an internal exchange of radicals, of

a diester itself obtained by the combination of I an omega-hydroxwester of the form U V V Ho.r:..(:ooia either with an organic acid R COOl-ior with a mineral acid AOI-I, the radical .R comprising at least 11 carbon atoms. This decomposition takes 7 place under the actionof heat with if necessary a reduction of pressure and in'the presence of a standard catalyst of the exchange of radicals.

As can be seen from the above, one of the important features of the present invention lies in the choice of the organic acid R COi-i (or oi the mineral acid AOH) and of the alcohol RF-OH so that by virtue of the high volatility of the ester lEt -COOR (or AOR the Reaction Ill can take place immediately and at a temperature low enough to enable-an excellent yield of monomeric lactone to be obtained. Thanks to the mildness of the reagents used and the conditionsv of preparation, the lactones obtained by this process are chemically-and oliactorily very pure. 7 V i No reaction of this type has been mentioned in 7 the-literature and this-new reaction is fundamental to the present invention. The only known reaction which could in certain directions 'be regarded as approaching that which'has just been described is the decomposition mentioned above'of'an ester of anoxyacid'HO.R.CO0-R with formation of a la'ctone Y :aooo

and an alcohol ROH (French Patent No.

830,689) but to make clear the essential difierences between the two processes, it suiiices to point out that: r

, a: The French Patent No 830.689 is concerned- -with an exchange reaction between an alcohol and an ester and not between two esters, or, what ,comes to the same thing, in the patent there'is formation of an alcohol as the second'product while in the process herein claimed there is formation of an ester as the second product.

and has a boiling point above 100 C. at a pressure of 2 mm. of mercury.

In the new process here described, exactly the opposite applies; the second oody formedwhich is here an ester-must be very volatile and distil over at a temperature substantially lower than does the lactone; in practice as will be seen from the examples given later, the ester formed at the same time as the lactone is gaseous under the conditions of the reaction and its' elimination is therefore instantaneous. V

c. In the French Patent No. 330,689 in order that the exchange reaction may take place it is essential to carry theheterogeneOus mixture'to a high'temperature and to eliminate'thelactone from thereaction zone when and as it is formed, utilising the well-known property of'polyols of carrying ofi less volatile bodies with theirvap-crs; this is the phenomenon of glycolic co-distillation which has been the subject of many investigations (of particularly Sabetay Ann. Chimie Analytique 1939, vol. 21, p. 173, and 1940, vol. 22, p. 217). 1

In the process here claimed there is nothing comparable; there is nopossibility of the lactone being'carried off by the ester formed and, the equilibrium being rapidly disturbed by the volatilization of the ester, the formation of the lactone' takes place very easily at arnuch lower temperature. It suflices thereafter to raise the 7 temperature slightly to distil 01f the l-actone unthought of as split into two sections B a-R comprises at least 11 carbon atoms in open chain and may reach a substantially higher figure; this,

radical R can be a straight or branched'chaing' it may be homogeneous, that is to say comprise only saturated radicals consisting only of carbon and hydrogen or it may be heterogeneous that is to say comprise one or more double or triple bonds, one or more hetero-atoms (such as oxygen, nitrogen, sulphur, etc.) whatever may be the internal linkingof these different radicals or groups;

Iheradical R of the acid"R COOI-l which esterifies the Oil of the hydroxyester can be hy-' drogen or a simple radical containing a low number of carbon atoms; thus the acid R -CQOH will be for example formic acid, acetic. acid, or one of their immediate homolcgues chosen so as to obtain after the reaction a very'volatile ester Similarly the mineral radical AO corre-.

sponding to the mineral acidAOI-l, alsO abieto esterify the OHof the hydroxy-estr will be chosen among the mineral acid radicals giving .with the alcohol Bi 0H a very volatile ester AORF; by way of an indicative and not limitatiye examplaboric, carbonictand sulphuric acids may be mentioned.

- Finally. the alcohol R -OH which esterifies the acidity of the omega-hydroxy acid HORLOOI-I will preferably be chosen among the lower alcohols, that is to say amongmethyl, ethyl, propyl,

butyl, etc. alcohols,;always with'a view to obtain- ,7 K

ing, along with the desired lactone, as volatile as here claimed, a body known for its properties .of

catalyzing theexchange of radicals will be used; without the list being intended to be limitative, the two following groups are particularly recommended: the alkaline or earth alkaline derivatives of moncor polyvalent alcohols orphenols; and more or less ionized bodies with an acid reaction, such as sulphuric or phosphoric acid, organic acids, arylsulphonic acids, etc.; it will be understood that the proportion of catalyst cannot be laid down in advance and will be determined in each case according to the activity of the catalyst and the speedof reaction it is desired to obtain; in a more general way, the present invention is not tied to the use of a particular catalyst.

The temperature and pressure will bechosen at the discretion of the operator according to the nature of the constituents of the reaction and their volatility.

The examples which follow will enable the possibilities of practising the invention to be appreciated; it will be understood that the examples are only given by way of indication; they in no way limit the invention which has been described above.

Example 1 Within the limits of experimental error, these constants are those of pure 1-16-hexadecanolide, given in the literature (Helv. C'him. Acta, vol. 11, 1171 (1928).

Example 2 25.7 grams of butyl-16-hydroxyhexadecanoate were converted into boric ester by means of 1.56 m. of boric acid. The water formed was driven off, the diester heated under a reduced pressure of 3 mm. of mercury in the presence of sodium methylate. With the heating bath at 180-190 Cta very mobile colorless liquid distilled off. This was collectedjit weighed 5.05 gm. This was butyl borate, for it distilled completelyat 122-124 C. under a pressure of 24 mm. of mercury, and at 97-99 C. under a pressure of 6 mm. of mercury; index of refraction n =1.4120 water hydrolyzed it into butanol and boric acid.

Heating under a vacuum was continued and when the temperature of the heating bath reached 230-240 C., 13.1 grams of distillate were collected in 2 hours, the constants of which were practically identical with those of the lactone ob tained in Example 1.

' Yield 64.8 per cent of theoretical.

Example 3 23.2 gms. of methyl-14-hydroxy-tetradecanoate were converted into boric ester by treatment with butyl borate. The butanol formed was driven .off, :thenzthe. excessof Jouty-lborate gsodium bytylate was introduced and heating was effected under a reduced pressure of 3 mm. of mercury. With the heating bath at 230-240 C., 12.5 gins. of distillate were collected during one hour.

The distillate was a colorless oil having an odor of musk, with the following characteristics:

Distilled completely between 110 and 112. .C. at

solidification point, 27 C.

Index of refraction 11. 1.4701

Density 014 0.9530

'Saponification value, 246.7

Within the limits of experimentalerror, these constants are those of 1-14-tetradecanolide.given in the literatur (Helv. Chim. Acta, vol. 11, 1171 (1928) )j.

Yield 61 per cent of the theoretical.

Example 4 20 grams of methyl-.Z-hydroxy-dodecanoate were converted into boric ester bytreatment with boric acid.

The diester was heated to 220-230 C. under a reduced pressure of 3 mm. of mercury, in the presence of sodium'methylate. In 80 minutes 10.1 mm. of distillate were collected.

This was a colorless oil, sprinkled with small shining white crystals. Its odor-was disagreeable; it recalled that of a burnt-out candle and of a mouldy cork bung, with a slight musty smell of mint.

Under fractional distillation, at2 mm. of mercury, these 10.1 gms., yielded between 83 and 85 C., 8.5 gms. of acolorless oil having the same odor, and 1.45 gm. of residue.

The distilled oil had the following characteristics:

Density r14 0.9800 Refractive index n 1.4715 Saponification value 280.7

Within the limits of experimental error these constants are those of 1-12-dodecanolide given in the literature (Helv. Chim. Acta, vol. 13, 1120 (1935-) Stoll and Rouve).

The yield was 49.3 per cent of the theoretical while Stoll and Rouv obtained only 16 per cent by the method of great :dilution.

The residue from the fractionation, twice recrystallized from alcohol, melted at 104 C. and had a saponi-fication value of 282.8. This is the theoretical "value for the dilactone for which Stoll and Rouv give a melting point of 101.

Example 5 23.7 gms. of methyl-,l-acetyloxy-IS-oxa-15- tetradecacarbanoate heatedto 220-230" C. under a reduced pressure of 3 of mercury, in the presence of sodium methylate, yielded 13.05 .gms. of distillate in a period of 70 minutes. This distillate was a colorless oil, having an odor of musk, distilling completely between and 112 C. at a pressure of 2.5 mm. of mercury. It "had the following constants:

solidification point C Density d4" 0.9950 Refractive index 12 1.4702 Molecular refraction R found 67.86 Calculated for C'14H26 O O O" 67.95 Saponification value 235.2

Calculated forCmHzeos V 68 percent of the theoretical.

Y i Example 6 V 28.8 g'ms. of methyl-1-hydroxy-4-oxa-16-pentadecacarbanoate were treated with boric acid.

The resulting diesterwas heated at 220-230 C. under a reduced pressure of 3 mm. of mercury, in the presence'of sodium methylate. 18.45 gms. of pure lactone were obtained, a yield of 72 per cent of the theoretical. It was a colorless liquid with 1 an odor of amber and musk, which had the following constants:

Boiling pointat 2 mm. of mercury C 113-115 Refractive index n 1.4683 Density d4 0.9853 Molecular refraction R found 72.25 Calculated for Ciel-I28 O' O' C)"w 72.45 Saponification value found 221.2 Calculated for cyclo -l-l-dioxa-pentadca-Z-carbanone i (CHEM-140E;

218.75 V (ensu -co Example 7 13-.80 gms. of methyl-16-acetyloxy-7-hexadecenoate were heated at 220250 under a reduced j, pressure of 3 mm. of mercury, in the presence of sodium methylate. 'In 1%. hours, 8.37 gms.

, ofdistillate were collected in the form or" a colorless oil having a strong'odor of musk.

' This distillate had the following characteris tics: g g H Redistilled at 3 mm. of mercury, it distilled over completelybetween -l iz and 144 C.

Density (14 Refractive index n 1.4816 Molecular refraction 'R found 74.98

Calculated for CieHsaOz (with a double bond between two atoms of carbon, one oxygen atom being linked with a carbon atom'through a double bond and the other atom of oxygen being'linked with a carbon atom through a single bond) 75.07 Saponification value; 224.0 Calculated for Ciel-12802 222.2 Iodine value (theory 100.7) 98.5

Within the limitsof experimental error, these constants are those of l'hexadecene 1.16'olide (ambrettolide) given. in 'the literature (Helv.

; Chim. Acta, V01. 17, 1612(1934) The yield of the operation in monolactone was "78.4 per centofthe theoretical; 1

As has already been mentioned, these exam-1, ples' are described'only by way of indication and not as limiting the invention; in particular the substances mentioned could, each in its category,

bereplaced by others having analogous proper-- tiesysimilarly the numerical particulars given 7 couldbe varied within wide limits without departing from the scope of the invention. V

What I claim is:

1; A method for producing substantially pure monocyclic lactones including at least 12 carbon atoms in the lactone ring, comprising providing at raised temperature and under reduced pressure, in the presence of a catalyst, the cyclization of a diester A-O(CH2) n-CO OR2 wherein n is an integer from 10 to .15 inclusive, R2 an alkyl radical selected from the group including methyl, ethyl, propyl and butyl, and A the radical of an acid adapted to produce an ester of high'volatility with the said alkyl radical, said reaction producing a lactone (CH2)n CO and an ester A-.O-Ri2 much more voltatile than the lactone, allowing said ester to evolve immediately in gaseous form and recovering the pure liquid lactone.

2. A method for, producing substantially pure wherein m is an integer from o to 3 inclusive and '11 is an integer from 10 to 15 inclusive, R2 an alkyl radical selected from the group including methyl, ethyl, propyl and butyl, said reac- 1 tion producing a lactone evolve immediately in gaseous form and recover{ ing the pure liquid lactone.

3. A method for producing substantially pure monocyclic lactones including at least 12 carbon.

atoms in the. lactone ring, consisting in providing at raised temperature and under reduced pressure, in the presence of a catalyst, the cyclization of a diester A-O(CI-I2) n.-COOR2, wherein n is an integer from 10 to 15 inclusive, R2 an alkyl radical selected fromthe group in cluding methyl, ethyl, ,propyl and butyl'and A the radical of an acid selected from the group consisting of boric, carbonic and sulfuric acids,

said reaction producing a lactone ems-co and an ester AO-Rz much more volatile than the lactone, allowing'said' ester toevolvejimmediately in gaseous form and recovering the pure liquidlactone. 7

LAURENT LUCIEQN' C ABALQNA.

References Cited-in'thefile oi this patent UNITED STATES PATENTS Number Name 1 Date M 1 7 2,234,551 Collaud -1- Mar. 11, 19 :1 2,301,827 Stoll- Nov. 10, 1942 2,417,151 I conaud Mar; 11,1947 

1. A METHOD FOR PRODUCING SUBSTANTIALLY PURE MONOCYCLIC LACTONES INCLUDING AT LEAST 12 CARBON ATOMS IN WHICH LACTONE RING, COMPRISING PROVIDING AT RAISED TEMPERATURE AND UNDER REDUCED PRESSURE, IN THE PRESENCE OF A CATALYST, THE CYCLIZATION OF A DIESTER 